The envelope protein from the human immunodeficiency virus (gp120) has been shown to produce neurotoxicity in both cell cultures of CNS-derived neurons and in the brains of rodents. We have extended these studies to examine if gp120 had a direct neurotoxic action on hippocampal neurons grown in cell cultures or if an indirect mode of action might explain the toxicity. In studies conducted by Dr. McCune, application of purified gp120 to hippocampal cultures which were highly enriched in neurons produced no detectible neuronal cell death. These cultures were virtually depleted of cells positive for glial fibrillary acidic protein, a marker for astroglia. Thus, a direct neurotoxic action for gp120 does not occur in this model system. Daily administration of 10 ng of gp120 (RFII strain) by intracerebroventricular cannula produced an impairment of learning in a spatial discrimination behavioral paradigm. These studies were extended with the testing of two other HIV-related envelope proteins: recombinant gp120 (SF2 strain) and recombinant gp160 with the IIIB encoding sequence. As observed with the native RFII and IIIB strains, the recombinant SF2 produced a significant retardation of learning acquisition in the Morris water maze test. In contrast, adult rats administered the recombinant gp160 responded at rates which were not different from that of saline- injected control animals.